Extensive experimental and clinical data have established that, at a concentration of approximately 1 ppm in drinking water, fluoride is highly effective in reducing the incidence of dental caries and does not cause adverse clinical responses. However, because of its well-documented cariostatic property, fluoride is increasingly being added to other dental health products, and the resulting increase in exposure of populations to fluoride has renewed consideration of the margin of safety which exists between the safe and toxic levels of fluoride exposure. There is cause for concern particularly in cases where fluoride metabolism may be altered by impaired physiological function. The objective of this study is, therefore, to determine the effects of chronic fluoride exposure on physiologically compromised animals in order to test the hypothesis that, under conditions of aging, metabolic or kidney diseases, or nutritional deficiencies, the biological impact of fluoride increases and the threshold for safe fluoride exposure is decreased. The specific aims of this project will be to monitor fluoride balance, terminal blood and tissue fluoride levels, changes in tissue integrity and function, and genetic alterations in animals chronically exposed to fluoride under conditions of: 1) aging; 2) diabetes; 3) chronic renal failure; and 4) nutritional deficiencies. Changes in the monitored parameters will be measured using biochemical, histological and genotoxic methodologies. If the effects of fluoride are increased, or become toxic, in these higher-risk animal populations and the hypothesis of this study is true, then data from this project will help establish awareness of the need for discriminant use of fluoride by similar high-risk human populations, and will clarify criteria for the safe, public health use of fluoride.